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10.1245/s10434-006-9097-6
Annals of Surgical Oncology 14:833-840 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Gallbladder Cancer: Defining the Indications for Primary Radical Resection and Radical Re-resection

Jason M. Foster, MD1, Hisakazu Hoshi, MD1, John F. Gibbs, MD1, Renuka Iyer, MD2, Miland Javle, MD2, Quyen Chu, MD1 and Boris Kuvshinoff, MD1

1 Department of Surgical Oncology, Roswell Park Cancer Institute, State University of New York at Buffalo, Elm & Carlton Streets, Buffalo, New York 14263-0001, USA
2 Department of Medical Oncology, Roswell Park Cancer Institute, State University of New York at Buffalo, Elm & Carlton Streets, Buffalo, New York 14263-0001, USA

Correspondence: Address correspondence and reprint requests to: Boris Kuvshinoff, MD; E-mail: boris.kuvshinoff{at}roswellpark.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The role of radical resection for gallbladder cancer is an ongoing area of debate. In this review, we present our experience managing gallbladder cancer at a tertiary center by using an aggressive surgical approach for T2 or greater disease, reserving simple cholecystectomy only for T1 lesions.

Methods: Seventy-six patients with histologically confirmed gallbladder cancer were identified from our cancer registry. Estimated survival distributions were calculated by the Kaplan-Meier method, and comparisons were made by using the log-rank test. The Cox proportional hazards model was used to determine the effect on survival of T stage, nodal status, age, and margins.

Results: Sixty-four patients were assessable for this study. Simple cholecystectomy was the only procedure performed in 10 T2 and 15 T3 cases. Radical cholecystectomy was performed as the primary procedure in two T2, two T3, and six T4 cases. Radical re-resection was accomplished in seven T2 and two T3 cases. Excluding the T4 group, there was a significant survival advantage (P = .007) for the radical resection group (n = 13; median survival not yet reached) compared with the simple cholecystectomy group (n = 25; median survival, 17 months; 95% confidence interval, 7–27 months). Analysis of the 13 T2 and T3 patients who underwent radical resections revealed that the radical re-resection group (n = 9) had an overall survival similar to that of the primarily resected group (n = 4). All T2N+ and T3N– patients are still alive and disease free after 5 years of follow-up, whereas none of the T3N+ or T4 patients survived beyond 24 months. Increasing T stage and age (>65 years) were independent predictors of a poor prognosis.

Conclusions: Radical resection for T2 and T3 disease resulted in a significant survival advantage compared with simple cholecystectomy. Patients who undergo radical re-resection after an incidentally discovered gallbladder cancer experience the same survival benefit as primarily resected patients. Radical resection for T2N–, T2N+, and T3N0 cases can achieve long-term survival. Conversely, the prognosis for T3N+ and T4 patients is poor, and improved outcome for this group will likely depend on the development of multi-institutional neoadjuvant clinical trials that can identify effective systemic regimens.

Key Words: Gallbladder cancer • Radical resection • Cholecystectomy • Re-resection


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Carcinoma of the gallbladder is the sixth most common malignancy of the gastrointestinal tract in the United States, with approximately 85,700 new cases annually.1 Most cases are diagnosed after symptomatic presentation, which is a late manifestation of this disease. The diagnosis can be protracted further because the symptoms are often those caused by biliary calculi, and gallstones are present in 80% of gallbladder cancers.2–4 Consequently, it is not surprising that the overall survival rate for this disease is only 5% to 10%.5,6

Although many therapeutic modalities have been used to treat gallbladder cancer, surgery remains the only curative modality. The selection of appropriate patients and the extent of surgery performed have been the subject of much debate. The surgical options available include simple cholecystectomy, nonanatomical gallbladder fossa resection, anatomical liver resection with regional node dissection, and sometimes bile duct resection with hepaticojejunostomy. The extent of surgery, in part, is governed by the extent of disease at presentation. One end of the clinical spectrum includes large symptomatic tumors that are amenable to complete resection, where an aggressive surgical approach is usually used with the dual goals of symptom relief and prolonged survival. The other end consists of small incidental tumors (Tis and T1) requiring only a simple cholecystectomy, which is curative in up to 95% of cases.2,7,8 The dilemma arises with the management of the T2 and T3 lesions that are often not diagnosed before surgery but are more commonly identified during surgery or pathologically after cholecystectomy. In these patients, the question of simple cholecystectomy versus radical resection or re-resection is a subject of debate.

Some groups believe that most T2 lesions require only a simple cholecystectomy, contending that radical resections are unnecessary and reserved for only the small subset of patients who meet pathologic criteria. These criteria include the presence of lymphovascular invasion or a depth of tumor invasion >2 mm.5,9,10 These groups also argue that T3 lesions have such a poor outcome that the risks of more radical surgery override the benefits, particularly in asymptomatic patients.

Proponents of radical resection believe that all T2 lesions should be treated with radical resection (primary or re-resection) because 40% of the patients will have residual or lymphatic disease at resection. More importantly, radical cholecystectomy is associated with a significant survival benefit—particularly now, when liver surgery can be performed with minimal mortality and acceptable morbidity.2,11–13 The T3 subset has an even higher chance of harboring residual local gallbladder fossa or regional nodal disease.14 Adjuvant therapies including radiation or chemoradiation are often given after resection, even though a survival benefit has not been definitively shown. Complete surgical resection remains the only curative option.

In this article, we present our experience with gallbladder cancer. The practice has been to offer radical surgery for suitable patients with this disease. Our hypothesis was that patients with T2 and T3 gallbladder cancer would benefit from a radical cholecystectomy (primary or re-resection) if an R0 resection could be performed.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients with histologically proven adenocarcinoma whose epicenter was located in the anatomical area of the gallbladder were identified at Roswell Park Cancer Institute in the tumor registry from January 1972 to April 2002. Retrospective chart reviews were conducted on 76 patients who satisfied the criteria. Patient demographics (age, sex, and presenting signs and symptoms), operations performed, 30-day surgical mortality, surgical morbidity, pathologic stage, adjuvant treatment, and survival were analyzed. Survival distributions were calculated by the Kaplan-Meier method, and comparisons were made by the log-rank test. Additionally, Cox proportional hazards analysis was performed on patients who underwent a radical resection to determine the effect of age ≥65 years, sex, T stage (T2 vs. T3 vs. T4), nodal status (N0 vs. N1 vs. N2), and margin status on survival. Staging was based on the 5th edition of the American Joint Committee on Cancer (AJCC) manual. Overall survival, the primary end point, was calculated as months from the first operation to death from any cause or the last clinical visit. All analyses were of an exploratory nature, and results were adjusted for multiple comparisons.

Simple cholecystectomy was defined as removal of the gallbladder by a laparoscopic or open approach. A radical resection always included (1) resection of the gallbladder and gallbladder fossa (anatomical or nonanatomical liver resections) and (2) node dissection, which routinely included the hilar, cystic, choledochal, hepatic, portal, celiac, and retropancreatic nodes along the right side of the superior mesenteric artery. The bile duct was resected as clinically indicated to achieve an R0 resection, whereas port sites were routinely resected in patients who had an initial laparoscopic cholecystectomy. Adjuvant 5-fluorouracil (5-FU)–based chemotherapy was given to all patients who had nodal involvement, whereas patients with a margin-positive resection received 5-FU–based chemoradiation. Palliative therapies were offered to patients with unresectable disease, including various combinations of surgical drainage, radiation, and chemotherapy.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of the 76 patients identified, 64 patients were eligible for analysis, with a median follow-up of 12.88 months (range 1–184 months), whereas 12 patients were excluded. Three patients were lost to follow-up and had no outcome data available. Three patients were excluded because they were found to have small-cell or neuroendocrine histopathology. Three were medically managed; another three were treated at an outside institution without pathologic results available for review.

White patients and women were four times more commonly affected than other ethnicities and men, respectively (Table 1Go). The median age was 64 years (range, 34–82 years). The most common presenting symptom was right upper quadrant pain, followed by epigastric pain and nausea (Table 2Go). The median duration of symptoms was 2 months. Porcelain gall-bladder was observed in only 8% (n = 5) of the patients, whereas gallstones were present in 75% (n = 48) of the patients.


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  		TABLE 1. Demographics for all patients
 

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  		TABLE 2. Presenting signs and symptoms
 
Sixteen patients had unresectable disease at presentation and underwent palliative care. Thirty-eight patients underwent initial simple cholecystectomy, 28 open and 10 laparoscopic, and 10 had primary radical resections. Patients who underwent simple cholecystectomy with T2 or greater disease (n = 34) were offered radical re-resection; only 10 patients (29%) both were medically fit and consented to the procedure. Nine of 10 of the patients underwent successful re-resection. One patient had unresectable disease at exploration and received palliative treatment.

Overall Outcomes
The median survival for all patients in this study, independent of stage or type of treatment, was 13 months (95% confidence interval [CI], 9–17 months), with a 5-year estimated survival rate of 22% (95% CI, 11%–33%). The estimated 5-year survival rate according to the type of treatment for all stages was 0%, 22% (95% CI, 6%–38%), and 42% (95% CI, 20%–64%) for palliation, simple cholecystectomy, and radical cholecystectomy (primary and re-resection), respectively (Fig. 1Go; P < .0001). The longest survivor in the palliation group died 20 months after initial presentation. The Cox proportional regression analysis on the radical resection subgroup revealed that increasing T stage and age >65 years were significant predictors of poor survival, whereas nodal status (N0 vs. N1 vs. N2) and margin status were not independent predictors (Table 3Go).


Figure 1
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  		FIG. 1. Survival curves for patients treated with palliation (dashed line), simple cholecystectomy (dotted line), and radical resection (solid line).

 

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  		TABLE 3. Cox proportional hazards model (n = 19; failure, n = 8)
 
T1 Patient Subset
Three patients had T1 disease and were treated with simple cholecystectomy. Specifically, one patient had a T1a lesion, and the other two patients had T1b lesions. Two patients (67%) survived 5 years, and the third patient died at 15 months. Pathologically this patient had a T1b lesion with evidence of lymphovascular invasion. Clinically, this patient experienced local disease recurrence at 5 months after cholecystectomy and was treated with 5-FU–based chemoradiation, with an initial response, but died of disease 10 months later.

T2 and T3 Patient Subset
Of the 64 patients with gallbladder cancer, 46 had pathologic T2 or T3 disease according to the AJCC 5th edition and represented the largest patient subgroup. Eight patients with T3 disease had unresectable disease at presentation and received palliative treatment. Of the remaining 38 patients (Table 4Go), 25 underwent simple cholecystectomy as definitive therapy (10 T2 and 15 T3). Radical resection was performed primarily in four patients (two T2 and two T3) and as re-resection after initial cholecystectomy in nine patients (seven T2 and two T3). The median time of follow-up for the 13 patients who had radical resections was 62 months (range 19–184 months). There were no surgical mortalities in either group, and in all radical resection cases a margin-negative (R0) resection was achieved. The incidence of node-positive disease in the resected T2 patients was 33% (three of nine) compared with 75% (three of four) in the T3 patients, including two T3 patients with N2 disease. The median survival for the simple cholecystectomy group (n = 25) was 17 months (95% CI, 7–27 months), whereas the median survival has not been reached in the radical resection group (n = 13; P = .007). The estimated 5-year survival was significantly higher in the radical resection group (62% [95% CI, 35%–99%] vs. 16% [95% CI, 0%–32%]; Fig. 2aGo).


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  		TABLE 4. Demographics, stage, survival, and adjuvant treatment for T2 and T3 patients
 

Figure 2
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  		FIG. 2. (a) Overall survival curves for patients treated with radical resection (solid line) for T2 and T3 gallbladder cancer compared with patients treated with simple cholecystectomy (dashed line). (b) T2 patients. (c) T3 patients.

 
The estimated 5-year survival rate for the T2 (n = 19) patients was 78% (n = 9; 95% CI, 50%–100%) and 38% (n = 10; 95% CI, 6%–70%) for the radical resection and simple cholecystectomy groups, respectively (Fig. 2bGo). Among the nine resected T2 patients, seven still have no evidence of disease, with survivals of 45 to 111 months. All T2 patients who had nodal disease (two N1 and one N2) survived, whereas the two deaths occurred after peritoneal recurrence in patients >65 years with N0 disease. The T3 (n = 19) patients had an estimated 5-year survival rate of 25% (n = 4; 95% CI, 0%–79%) and 0% (n = 15) for the radical resection and simple cholecystectomy groups, respectively (Fig. 2cGo). The longest-living patient in the T3 simple cholecystectomy group survived only 33 months. Of the three patients who died in the radical resection group, two had N2 disease, and the exact nodal status of the third patient was not available; the survivor had T3N0 disease.

Radical Resection Compared With Re-Resection
A total of 19 patients underwent radical resections, with 10 primary resections (2 T2, 2 T3, and 6 T4) and 9 re-resections (7 T2 and 2 T3). The median survival for the primary resected group was 11 months (95% CI, 7–14 months), and the median survival has not been reached for the re-resection group. Outcomes with these groups were significantly different, with estimated 5-year survival rates of 10% (95% CI, 0%–28%) vs. 78% (95% CI, 50%–100%), respectively (data not shown). Because all of the T4 patients (n = 6) were in the primarily resected group and half of them (3 of 6) had margin-positive (R1) resections, the analysis was performed with this group excluded. There was not a statistically significant survival difference between the primarily resected and re-resected T2 and T3 patients (Fig. 3Go).


Figure 3
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  		FIG. 3. Overall survival curves for T2 and T3 patients treated with radical re-resection (solid line) compared with those treated with primary radical resection (dashed line). N.S., not significant.

 
Palliation Group
Sixteen patients presented with unresectable disease and were treated with supportive care, surgical palliation, radiation, chemotherapy, or some combination of these modalities. Three patients required biliary diversion, and one patient required both biliary and enteric bypasses. Systemic therapy or radiation was given to 11 patients: 2 with radiation alone, 4 with 5-FU–based chemotherapy, and 5 with chemoradiation. Five patients were given supportive care alone. The median survival for these 16 patients was 8 months (95% CI, 5–10 months), and no patient survived longer than 20 months. In this small subset of patients, the addition of systemic therapy or radiation did not influence survival.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Gallbladder cancer continues to carry a poor prognosis.5,6 The only consistent curative therapy for gallbladder cancer is surgical resection. Only 15% to 40% of the patients who present with gallbladder cancer are candidates for operative intervention, thus leaving most of these patients without effective treatment options.6 Of the patients who undergo extended resections, most studies have found that T stage (>T2), the presence and extent of nodal involvement, and the inability to perform a margin-negative (R0) resection predict poor survival.12,15 Nodal involvement is consistently one of the strongest predictors of a poor outcome.12,15,16

In this retrospective study, we found that patients with T2 and T3 disease derived a survival benefit from radical resection (Fig. 2Go). All of the T2 and T3 radical resections were margin negative (R0), whereas half of the T4 radical resections were margin positive (≥R1). The variables found to be poor prognostic factors in this small study included T stage and patient age, whereas nodal status and R0 (margin) status had no statistically significant effect on survival. Additionally, performing radical re-resection rather than primary radical resection was not associated with decreased survival in stage-matched patients.

Previous series supporting radical resection have found nodal disease to be present in up to 45% of patients with T2 disease and in 60% to 70% of patients with T3 disease; these results are similar to the data found in our series.12,14 There is an equally high chance that residual disease will be found in the liver or adjacent bile ducts. Groups that implement an aggressive surgical approach have achieved 5-year survival rates of 60% to 90% for T2 disease and 30% to 60% for T3 disease.11 Because of the small sample size, we combined the T2 and T3 groups and found an improved 5-year survival rate of 62% (95% CI, 35%–99%) in the radical resection group and 16% (95% CI, 0%–32%) for the simple cholecystectomy group. These results are consistent with previously reported results.11–13

Most data over the past 15 years have identified the T2 group as the subset that derives the greatest benefit from extended resection. Simple cholecystectomy yields 5-year survival rates ranging from 19% to 41%, whereas extended resection 5-year survival rates range from 60% to 100%.8,17–20 Our experience was quite similar, with a 5-year survival rate of 38% for simple cholecystectomy compared with 78% for radical cholecystectomy. Our incidence of nodal involvement was 33% (three of nine), including one patient with N2 disease [superior mesenteric artery (SMA) node], consistent with the reported rate in the literature.12,18,21–23 Contrary to other reports, nodal involvement did not adversely affect the survival of our T2 patients.12,15,16 All of our node-positive T2 patients were cured and are alive with follow-ups ranging from 75 to 105 months. Two factors may have contributed to this unexpected outcome. First, in our surgical approach, we routinely performed nodal dissections as described by Shimada et al.,14 which includes taking the nodes to the right of the SMA. Initially, this was based on knowledge of the embryological contribution of the midgut to gall-bladder lymphatic drainage. Recently, anatomical studies have validated metastatic lymphatic involvement behind the pancreas along the SMA. Contrary to Shimada et al., who found that when this nodal group was involved, patients died within 2 years, our N2 patient is still alive with no evidence of disease at 75 months. Second, all patients with nodal disease received adjuvant chemotherapy. Unfortunately, there is a lack of available data to evaluate the effect of chemoradiation in this population.

There are groups who propose that not all T2 lesions should be treated with aggressive resection and that it should be reserved for T2 lesions with a >2-mm depth of invasion or the presence of lymphovascular invasion.9 On the basis of our data, we challenge these recommendations and believe that all T2 lesions should be treated with aggressive resection. However, it may be appropriate to apply these criteria to T1 lesions. In this study, there were only three T1 cancers, and two (67%) patients survived 5 years after simple cholecystectomy. Prior studies of T1 gallbladder cancer have shown that simple cholecystectomy results in 5-year survival rates of 80% to 95%, and this has become the accepted surgical approach.2,7,8 This suggests that up to 20% of patients with T1 disease will have occult disease beyond the gallbladder at presentation. Some groups have carefully analyzed their T1 failures and suggest that an aggressive surgical approach be implemented for the T1b subset of gallbladder cancer.17,24,25 Recently, the AJCC split T1 cancers into T1a, tumors confined to the mucosa, and T1b, tumors confined to the muscularis. The recognition that lymphovascular invasion is present in up to 30% of patients with T1b disease has stimulated groups to examine their failures.17 Ouchi et al.25 treated 11 T1 patients with simple cholecystectomy. Four of these patients had T1b disease, with two of these patients dying from recurrence, whereas none of the T1a patients had recurrence. Wagholikar et al. reported similar results. They had 14 patients, 12 of whom had T1b disease.24 Five disease-related deaths occurred, all in patients with T1b lesions. These findings identify patients with T1b disease as a group at risk for disease recurrence, and studies using radical resection and adjuvant therapy need to be considered for this subset. Our small experience with T1 disease parallels these findings; our failure was a T1b patient who had lymphovascular invasion.

In locally advanced gallbladder cancer (AJCC 5th edition T3 and T4), the value of extended resection is more controversial. Previous reports in the literature concluded that patients in this group, when treated with only simple cholecystectomy, die within 2 years of recurrent disease, whereas aggressive resection results in 5-year survival rates ranging from 10% to 40%.12,18,21,26 In our study, the estimated 5-year survival rate for the T3 radical resection group was 25% (95% CI, 0%–69%), compared with 0% with simple cholecystectomy (the longest survival was 33 months). Although the T3 resection group was a small subset of four patients, it was notable that the only patient to survive was node negative (N0). The three patients who succumbed to nodal disease had primarily N2 disease. This is consistent with other investigators’ results, in which N2 disease in T3 patients is incurable, with survivals of 18 to 36 months.27 No patient in our T4 group, regardless of nodal status, survived 5 years (the longest survival was 23 months). However, most T4 patients in the resection group had relief of their preoperative symptoms without significant morbidity or any mortality.

The optimal timing of extended resection has been debated, but no prior study has compared its effect by using stage-matched groups. We compared the effect of primary resection with that of re-resection in our T2 and T3 groups. The estimated 5-year survival rate of the re-resection group was higher, at 78% (95% CI, 50%–100%), compared with 25% (95% CI, 0%–69%) for the primary resected group, but this was not statistically significant (Fig. 3Go). This can be explained by three factors. First, the obvious factor is that our sample sizes were small. Second, the primary resection group had a higher proportion of T3 tumors (50% vs. 22%). This is significant because the estimated 5-year survival rate was 78% for T2 disease and was only 25% for T3 disease (Fig. 4Go). Finally, re-resection allows time for patients with unfavorable tumor biology to experience disease progression and be excluded from resection. The fact that there was no adverse effect in performing radical re-resection is encouraging, but we still prefer to perform primary resection if that option is available. The benefits of performing the resections in a primary setting include a technically less demanding operation, which may require a less extensive resection because there are no postoperative changes in the field. However, because most patients are referred weeks after their cholecystectomy, re-resections are more commonly performed. It is important to recognize that our data show no survival disadvantage to performing re-resection, although patient selection for a second operation make direct comparisons problematic.18


Figure 4
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  		FIG. 4. Overall survival curves for patients with T2, T3, and T4 disease who underwent radical resection.

 
Currently we perform radical resections in all patients with T2 lesions. For T3 patients, we perform radical resections in patients without gross evidence of nodal disease or in patients with gross nodal (N1) involvement who have shown disease stability or regression with neoadjuvant therapy. All resected T2 and T3 patients found to have microscopic nodal disease or a positive margin receive adjuvant therapy. The primary chemotherapy regimen used in this study was 5-FU based. However, we are currently using 5-FU in combination with gemcitabine, irinotecan, or oxaliplatin.

In summary, our study suggests that T stage and advanced age are strong predictors of survival. The unfavorable effect of advanced age in this study is unclear and will require further investigation. More importantly, aggressive resection results in a significant survival benefit for T2 and T3 disease. This held true for patients with node-positive T2 disease and node-negative T3 disease, given that all of these patients were alive at 5 years. The approach to the node-positive T3 patient could be refined by enrolling patients with pathologically positive nodes onto postoperative adjuvant protocols and by entering patients with clinically evident nodal disease onto neoadjuvant protocols. Our data support the feasibility of a neoadjuvant approach because radical resections performed in a delayed fashion did not result in any survival detriment.

Clearly, more effective screening strategies concomitant with the development of better adjuvant therapies will aid in improving the overall outcome in this disease. Even when these modalities are discovered, radical resection will still remain a core component in the management of this disease.


   FOOTNOTES
 
Presented at the 58th Annual Meeting of the Society of Surgical Oncology, Atlanta, Georgia, March 3–6, 2005.

Received for publication May 23, 2006. Accepted for publication May 23, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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S. J. Kim, J. M. Lee, J. Y. Lee, J. Y. Choi, S. H. Kim, J. K. Han, and B. I. Choi
Accuracy of Preoperative T-Staging of Gallbladder Carcinoma Using MDCT
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